title: Coumarin-purine ribofuranoside conjugates as new agents against hepatitis C virus.
abstract: About 3% of world's population is infected by the hepatitis C virus (HCV), for which prophylactic vaccine is not available yet. Nowadays, pegylated interferon-α and ribavirin are commonly used to treat HCV; unfortunately these drugs often produce significant side effects. Upon the desperate need of anti-HCV drugs, a plan to establish a new compound library was set that included leads with high antiviral activity, good hydrophilicity, yet low toxicity. Accordingly, 26 new conjugated compounds were synthesized through the chemical coupling of various 9-(β-D-ribofuranosyl)purine-8-thiones with 3-(chloromethyl)coumarins bearing various substituents. A -SCH(2)- unit was used to link the coumarin and the purine moieties. The three hydroxyl groups at the 2'-, 3'-, and 5'-positions were selectively protected with an acyl or acetal group in these coumarin-purine ribofuranosides. Their anti-HCV and cytostatic determination assays were performed, and the structure-activity relationship was established. Three conjugates in the family of 8-(coumarin-3'-yl)methylthio-9-(β-D-ribofuranos-1''-yl)purine possessed an appealing ability to inhibit HCV replication with EC(50) between 5.5 and 6.6 μM and EC(90) of ∼20 μM. These data in the new compound library provide clues for the future in the development of anti-HCV leads for viral eradication.
authors.affiliation: Department of Chemistry, National Tsing Hua University , Hsinchu, Taiwan 30013, ROC. jrhwu@mx.nthu.edu.tw
authors.forename: Jih Ru
authors.initials: JR
authors.lastname: Hwu
authors.forename: Shu-Yu
authors.initials: SY
authors.lastname: Lin
authors.forename: Shwu-Chen
authors.initials: SC
authors.lastname: Tsay
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Pieter
authors.initials: P
authors.lastname: Leyssen
authors.forename: Johan
authors.initials: J
authors.lastname: Neyts
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D003374:Coumarins / Q000737:chemistry*; D055808:Drug Discovery; D005663:Furans / Q000737:chemistry*; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006878:Hydroxides / Q000737:chemistry; D008958:Models, Molecular; D008968:Molecular Conformation; D011684:Purine Nucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012263:Ribonucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D003374:Coumarins; D005663:Furans; D006878:Hydroxides; D011684:Purine Nucleosides; D012263:Ribonucleosides; C031356:hydroxide ion; C030123:coumarin; C005248:nebularine; C039281:furan